Until the 20th Century, influenza, pneumonia, tuberculosis, and diarrhea/enteric diseases were the top three causes of death in Western countries. The average life expectancy of adults was less than 50 years, and 2% of children failed to live beyond age 5 years.
Industrialization and growing wealth in the 19th century brought improvements in sanitation and drinking water, leading to dramatic reductions in communicable enteric infections. By the early 20th century, vaccines for pertussis, tuberculosis, diptheria and yellow fever were being developed and tested in clinical trials. However, life-threating bacterial infections remained a common threat. Strep throat was sometimes a fatal disease, ear infections could lead deafness, mastoiditis or meningitis with a 90% mortality rate, and surgery or childbirth was much more dangerous.
Figure 1. Changes in life expectancy over 500 years
The microbiologist and immunologist Paul Ehrlich (1854-1915) is generally credited with the first discovery of an antibiotic for the medical treatment of syphilis-arsphenamine or Salvarsan. The term “antibiotic” was later introduced by in 1943 by Selman Waksman-the discoverer of streptomycin. Erlich’s approach of screening synthetic libraries of chemicals for selective antimicrobial properties was the basis of early antibiotic research and led to the discovery of the first sulfa antibiotics (e.g., sulfamidochrysoidine, sulfanilamide).
However, it was the serendipitous discovery of penicillin on September 3, 1928 by Alexander Fleming and the subsequent purification of the drug in quantities needed for clinical testing by Florey and Chain in the late 1930s eventually led to mass production and distribution of penicillin by 1945- ushering in the modern antibiotic age. Alexander Fleming was also among the first to cautioned about the potential resistance to penicillin if used too little or for a too short of period during treatment.
It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. -Sir Alexander Fleming
Indeed, Fleming’s predictions were proven to be true within a couple of years, with the first case of penicillin resistance reported in 1947. Thus began an “arms race” between discovery or novel antibiotics and antimicrobial resistance.
Although resistant infections were frequently encountered in the early days of antibiotic use, a flow of new antibiotics from 1950s-1980’s provided alternative treatments. It was possible to simply switch treatment once resistance against a specific antibiotic became a major problem. But then the antibiotic discovery began to slow. The latest discovery of a new antibiotic class that has reached the market was in 1987. Since then, there has been a lack of innovation in the field, and today there are few novel antibiotic classes in the drug pipeline. In Module 2 we will scientific and market forces that have made new antibiotic discovery increasing difficult in both in both developed and low-middle-income countries (LMICs)
Once a resistant bacterium has developed, it can spread from a colonised person to another person if appropriate hygienic precautions (e.g., hand hygiene, isolation) are not taken. The risk of resistant bacteria spreading is enhanced in crowded environments, especially when people in the surrounding area are receiving antibiotics - a common situation in hospitals and other healthcare facilities.
The consequences of faltering antibiotic discovery are now seen worldwide as more and more bacterial infections are becoming hard to treat once again. Especially worrisome is the lack of antibiotics against Gram-negative bacteria. The rapid global spread of multi- and pan-resistant bacteria (also known in the lay press as “superbugs”) can cause infections that are not treatable with existing antibiotics.
Figure 2. Antibiotic discovery timeline
Recognizing the growing global threat of antibiotic resistance (AMR) on human health but also the economy and human development, The World Health Organization (WHO) in 2017 developed a Global Action Plan on AMR. The global health plan outlines 21 strategies and 5 strategic objectives of a national action plans to addressing AMR.
The WHO also published a Priority Pathogen List for research and development of new antibiotics. This list is in addition to Mycobacteria (including Mycobacterium tuberculosis, the cause of human tuberculosis), which was globally established priority for which innovative new treatments are urgently needed The list breaks down pathogens into three priority groups:
| Priority group | Pathogens included |
|---|---|
| Critical | Acinetobacter baumannii (Carbapenem-resistant) Pseudomonas aeruginosa (Carbapenem-resistant) Enterbacterales (3rd generation cephalosporin, carbapenem-resistant) |
| High | Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter, fluoroquinolone-resistant Salmonella spp., fluoroquinolone-resistant Neisseria gonorrhoeae, 3rd generation cephalosporin-resistant, fluoroquinolone-resistant |
| Medium | Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., fluoroquinolone-resistant |
Southern Europe, including Italy have among the highest resistance rates of WHO “critical pathogens.” For example, surveillance data from the European Centres for Disease Control (ECDC) have documented a dramatic increase in carbapenem-resistance in Italy since 2009 with now more than one-third of Klebsiella pneumoniae resistant to previously-considered last-line antibiotics such as carbapenems. (see link to interactive resistance atlas here) Similarly, the The Italian Micronet Resistance Surveillance program reported that:
Figure 2. Regional difference in CRE bloodstream infection incidence per 100,000 residents in Italy. Source:Micronet https://www.epicentro.iss.it/antibiotico-resistenza/cre-dati
In 2017, a report by the the ECDC noted that the AMR situation in Italian hospitals and regions poses a major public health threat to the country. The levels of carbapenem-resistant Enterobacteriaceae (Enterobacterales) (CRE) and Acinetobacter baumannii have now reached hyper-endemic levels and, together with methicillin-resistant Staphylococcus aureus (MRSA), this situation causes Italy to be one of the Member States with the highest level of resistance in Europe. During conversations in Italy, ECDC often gained the impression that these high levels of AMR appear to be accepted by stakeholders throughout the healthcare system, as if they were an unavoidable state of affairs. The factors that contribute negatively to this situation seem to be:
Because the drivers of antimicrobial resistance lie in humans, animals, plants, food and the environment, a sustained One Health response is essential to engage and unite everyone around a shared vision and goals.
“One Health” refers to designing and implementing programmes, policies, legislation and research in a way that enables multiple sectors engaged in human, terrestrial and aquatic animal and plant health, food and feed production and the environment to communicate and work together to achieve better public health outcomes.
Figure 3. A One Health response to address the drivers and impact of antimicrobial resistance. From https://www.who.int/docs/default-source/documents/no-time-to-wait-securing-the-future-from-drug-resistant-infections-en.pdfsfvrsn=5b424d7_6
Third generation cephalosporins (ceftotaxime, ceftriaxone) are widely used for serious infections in humans, including urinary tract, abdominal, lung and bloodstream infections and are classified as “critically-important” for human health (WHO AGISAR). Cetiofur, cefpodoxime, and cefoperazone are 2nd and 3rd generation cephalosporins appoved for veterinary use and predominantly for treating bacterial infections in food-producing animals including chickens and cattle.
Resistance to 3rd generation cephalosporins is mediated by extended-spectrum beta-lactamases (ESBLs) and AmpC. ESBL genese are highly mobile and transmitted on plasmids, transposons and other genetic elements. Resistance to 3rd generation cephalosporins is common among Escherichia coli and Klebsiella pneumonia requiring greater rela
Figure 4.Antibiotic use in animals
European flight patterns, 2014